Despite widespread use of anti-retro viral therapy, neurological disorders continue to contribute significantly to the morbidity and mortality associated with HIV infection. The immunological correlates of protection against neuropathogenic progression of HIV infection have not been characterized, but an understanding of the neuroprotective and neurodegenerative roles played by host immunity is central to effective vaccine development. Studies using the simian immunodeficiency virus (SIV) model have shown that CD8+ lymphocytes protect against rapidly fatal SIV encephalitis (SIVE) during acute infection; however, the relative contribution of humoral immunity to protection against SIVE during acute and chronic infection remains unknown. This research program will use the neurovirulent SIVsmmFGb model to specifically investigate the effects of neutralizing antibodies (nAbs) on brain virus burden and SIVE. Using this model, we have found that macaques with detectable nAb responses at 1 month post inoculation (mpi) resist SIVE even in the absence of measurable cell-mediated responses at 3 mpi. We hypothesize that nAbs are particularly effective in the CNS, where neutralization-sensitive macrophage-tropic viruses predominate. Furthermore, we hypothesize that nAbs supplement cell-mediated protection against SIVE during acute infection and limit the extent of viral reactivation in the CNS during chronic infection. To test these hypotheses, in Aim 1 we will correlate the magnitude and quality of nAbs in blood and CSF with brain virus burden and markers of SIVE throughout the course of SIVsmmFGb infection, paying particular attention to the effect of nAbs on (1) autologous virus isolates and on (2) virus replication in macrophages. We hypothesize that nAb liters will be correlated with protection against SIVE, particularly in macaques with suboptimal antiviral cellular immunity. In Aim 2, we will determine the impact of humoral immunity on SIVE pathogenesis by depleting CD20+ B cells before SIVsmmFGb infection and evaluating the neuropathogenic outcome. We hypothesize that CD20-depleted macaques with suboptimal cellular immunity will develop SIVE due to impaired nAb responses, while non-depleted macaques with intact nAb responses will resist SIVE. In Aim 3, we will use a passive therapy approach to examine the effect of nAbs on SIVE during acute SIVsmmFGb infection. We hypothesize that passive therapy with SIV-immune globulin (SIVIG) will promote de novo production of nAbs, and that SIVIG-treated macaques will have lower brain virus burdens and resist SIVE longer than controls. The results of these studies will help gauge the relevance of including methods to generate nAbs in addition to antiviral CTL in the development of vaccines designed to protect against the numerous and diverse sequelae of HIV infection.